The present invention relates to methods of treating disorders associated with abnormal phosphate metabolism, and more particularly to the use of regulators of GalNAc-T3 in the treatment of disorders associated with hyperphosphatemia such as Familial tumoral calcinosis (FTC), hyperphosphatemic calcinosis, hemodialysis, and chronic renal failure, as well as disorders associated with hypophosphatemia, e.g., X-linked vitamin D resistant hypophosphatemic rickets (HYP), hereditary hypercalciuria with hypophosphatemic rickets (HHRH), oncogenic hypophosphatemic osteomalacia (OHO), and X-linked hypophosphatemic rickets (PHEX).
Phosphate-related abnormalities (i.e., hypophosphatemia or hyperphosphatemia) characterize a class of metabolic disorders manifesting with hyper-and dys-lipidemia, rickets and/or serious metastatic calcification, which can eventually lead to death. These disorders result from disrupted phosphate metabolism. Inorganic phosphate is absorbed in the intestinal tract in a process regulated by 1α, 25-dihydroxyvitamin D3 (vitamin D3). On the other hand, phosphate excretion, which is regulated by the parathyroid hormone, takes place in both kidney and intestinal tract (i.e., fecal excretion). Moreover, the liver, skin and kidney are involved in the conversion of vitamin D3 to its active metabolite, calcitriol, which plays an active role in maintaining phosphate balance and bone mineralization.
Under normal conditions, a decrease in plasma phosphate level stimulates the production of vitamin D3 in the renal proximal tubule, resulting in increased absorption of calcium and phosphate. The increase in calcium level leads to a secondary suppression of the parathyroid hormone (PTH), which results in upregulation of the sodium-dependent phosphate transport in the renal proximal tubule.
Hyperparathyroidism, a condition characterized by overproduction of PTH in the parathyroid glands, results in hypophosphatemia and increased phosphate excretion due to inhibition of sodium-dependent phosphate transport in the kidney.
Other conditions which involve hypophosphatemia include vitamin D deficiency, which causes rickets in children and osteomalacia in adults, X-linked vitamin D resistant hypophosphatemic rickets (HYP), hereditary hypercalciuria with hypophosphatemic rickets (HHRH), Dent's disease including certain types of renal Fanconi syndrome, renal I alpha-hydroxylase deficiency (VDDR 1), defects in 1,25-dihydroxy vitamin D3 receptor (end organ resistance, VDDR II), oncogenic hypophosphatemic osteomalacia (OHO), and X-linked hypophosphatemic rickets (PHEX) [Francis, Nat. Genet. (1995), 11: 130-136; Rowe, Hum. Genet. (1996), 97: 345-352; Rowe, Hum. Mol. Genet. (1997), 6: 539-549).
On the other hand, hyperphosphatemia, i.e., increased plasma level of PO4, is often a result of renal insufficiency. End-stage renal insufficiency, a condition affecting approximately 250,000 individuals in the USA, can lead to metastatic calcification, i.e., the deposition of calcium phosphate in previously healthy connective tissues and solid organs. Thus, advanced renal failure, i.e., a glomerular filtration rate of less than 20 mL/min, causes a decrease in PO4 excretion and an increase of plasma PO4. However, other conditions may also decrease PO4 excretion. These include pseudohypoparathyroidism or hypoparathyroidism. Hyperphosphatemia can also result from excess administration of oral PO4, or from overuse of enema containing phosphate salts. Furthermore, hyperphosphatemia may result from migration of intracellular PO4 to the cell exterior. Such migration frequently occurs in diabetic ketoacidosis (regardless of systemic PO4 loss), bruise, non-traumatic rhabdomyolysis, systemic infection and tumor lysis syndrome. Moreover, hyperphosphatemia plays a critical role in the onset of secondary hyperparathyroidism, and the onset of renal osteodystrophy in patients under dialysis treatment for a long period.
Familial tumoral calcinosis (FTC; MIM211900) is a severe autosomal recessive metabolic disorder manifesting with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues, especially of the hips and knees. Hyperphosphatemia, secondary to increased renal phosphate retention, is the major metabolic abnormality associated with familial tumoral calcinosis (FTC) and is accompanied by inappropriately normal or elevated levels of PTH and 1,25-dihydroxyvitamin D3, two essential regulators of phosphate metabolism [Steinherz, 1985 (Supra)]. While hyperphosphatemia appears in FTC patients as early as 21 months of age, the calcium deposits are noted later in childhood. Thus, all FTC patients have elevated serum phosphorus levels, and in some patients, elevated levels of 1,25-vitamin D are also detected. FTC represents the metabolic mirror image of hypophosphatemic rickets caused by mutations in PHEX (MIM307800) and in FGF23 (MIM193100) genes [Schiavi, S. C. and Kumar, R. Kidney Int. 65, 1-14 (2004); Quarles, L. D. Am. J. Physiol. Endocrinol. Metab. 285, 1-9 (2003)] and which is characterized by decreased phosphate levels, decreased renal tubular phosphate reabsorption and inappropriately normal or decreased levels of 1,25-dihydroxyvitamin D3 [Prince M. J. et al. Ann Intern Med. 96, 586-591 (1982)].
Current treatment regimens of hypophosphatemia related disorders [e.g., hypophosphatemic rickets (PHEX)] include active vitamin D analogues (e.g., calcitriol) and oral phosphate supplementation. However, both of these nutrition supplements often fail to normalize serum phosphate level and in many cases, the patients fail to reach normal adult height. The recent use of recombinant human growth hormone (rhGH) was reported to benefit children with PHEX, however, is often associated with disproportional growth of the trunk (Reviewed in Reusz G, 2001, Orv Hetil. 142: 2659-65; Wilson D M 2000, J. Pediatr. Endocrinol. Metab. Suppl 2: 993-8).
Treatment of hyperphosphatemia involves the use of aluminum- or calcium-based phosphate-binding agents, which effectively lower serum phosphorus levels. However, while the use of aluminum-based agents can be associated with bone toxicity, renal osteodystrophy and encephalopathy, the use of calcium-based agents is often associated with hypercalcaemia and cardiovascular calcification. To overcome these limitations, non-calcium-, non-aluminium-based alternative agents were developed. These include the sevelamer hydrochloride and lanthanum carbonate (Hutchison A J, 2004, Nephrol Dial Transplant. 19 Suppl 1:i19-24; Chertow G M., 2003, J Am Soc Nephrol. 14: S310-4). However, while lanthanum was found to be effective and well-tolerated (Joy M S et al., 2003, Am. J. Kidney Dis. 42: 96-107), sevelamer was found to be less effective than aluminum (Cizman B. 2003, Nephrol. Dial. Transplant. 18 Suppl 5:v47-9) and the use of both of these agents is limited by their high cost. Moreover, both of these agents treat only the symptoms by suppressing phosphate re-absorption in the intestinal track and not the causes which lead to hyperphosphatemia.
Thus, there is a need to develop pharmaceutical compositions and methods of treating disorders associated with phosphate metabolism devoid of the above limitations.
Phosphatonin is a novel circulating phosphaturic factor, postulated to be primarily responsible for modulating urinary phosphate excretion in a variety of hypophosphatemic disorders.
Quarles, 2003 (J Clin Invest. 112: 642-646), suggested that phosphatonin is a circulating protein that inhibits sodium-dependent phosphate reabsorption in the renal proximal tubule via mechanisms which are distinct from PTH, and vitamin D3. The fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (SFRP4) and matrix extracellular phosphoglycoprotein (MEPE) [Schiavi, S. C. and Kumar, R. Kidney Int. 65, 1-14 (2004); Quarles, L. D. Am. J. Physiol. Endocrinol. Metab. 285, 1-9 (2003)] were suggested as the putative phosphatonin proteins since they modulate circulating phosphate levels [Shimada, T. et al. Proc Natl Acad. Sci. 98, 6500-6505 (2001); Bowe A. E. et al. Bioch Biophys Res Comm. 284, 977-981 (2001); Rowe P. S. N. et al. Bone. 34, 303-319 (2003); Berndt, T. et al. J. Clin. Invest. 112, 785-794 (2003)].
Thus, FGF23 and other phosphatonin genes have been considered as prime candidates for the FTC gene [Jan De Beur, S. M., and Levine, M. A. (2002), J. Clin. Endocrinol. Metab. 87: 2467-2473].
While reducing the present invention to practice, the present inventors have uncovered that mutations in GALNT3 gene encoding UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T3) cause FTC. Thus, inducers of GalNAc-T3 can be used to treat hyperphosphatemia related disorders such as FTC, and on the other hand, inhibitors of GalNAc-T3 can be used to treat disorders associated with hypophosphatemia, such as hypophosphatemic rickets.